BCH-BB694 — an experimental gene therapy targeting the BCL11A gene — safely increased the levels of fetal hemoglobin and prevented disease-associated complications in six people with severe sickle cell disease (SCD), according to interim data from a Phase 1 clinical trial.
These findings further support the feasibility and therapeutic value of approaches targeting BCL11A, which is involved in the suppression of fetal hemoglobin in adult red blood cells.
Trial findings were reported in the study, “Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease,” published in The New England Journal of Medicine.
BCH-BB694, developed by a team of researchers at Boston Children’s Hospital led by David Williams, MD, uses a modified and harmless virus to promote the production of fetal hemoglobin in blood precursor cells (hematopoietic stem cells) collected from a patient.
The virus was created in collaboration with Bluebird Bio, and delivers a genetic sequence with the instructions to produce a microRNA that suppresses BCL11A’s activity in red blood cells.
MicroRNAs are small RNA molecules that target a specific gene’s messenger RNA — the genetic blueprint derived from DNA and used as a template for protein production — to prevent generation of that protein.
The modified cells are re-introduced to the patient in the form of a stem cell transplant, following myeloablative chemotherapy to kill cells in the bone marrow, thereby lowering the number of blood-forming cells. This way, the stem cell transplant will have a better chances of rebuilding a healthy bone marrow.
Of note, fetal hemoglobin is a form of hemoglobin produced during fetal development that is more effective at transporting oxygen than its adult counterpart. By increasing the levels of fetal hemoglobin, BCH-BB694 is expected to lower the frequency of SCD complications, such as vaso-occlusive crises (VOCs) and acute chest syndrome.
Based on positive data from preclinical studies, Williams is sponsoring a two-year, pilot Phase 1 trial (NCT03282656) to evaluate the feasibility, safety, and preliminary effectiveness of a single administration of patients’ own blood precursor cells modified with BCH-BB694 to people with severe SCD.
Patient recruitment at Boston Children’s Hospital and UCLA Mattel Children’s Hospital in Los Angeles may still be ongoing; more information can be found here. Those who finish two years of follow-up may choose to enter a 13-year long-term follow-up study.
Six of the nine enrolled patients as of October 2020 had at least six months of follow-up data, and were included in the interim analysis. Their age at enrollment ranged from 7 to 25, and they were followed for a median of 18 months (range, seven to 29 months) after treatment.
Results showed that BCH-BB694 treatment was generally safe, with most adverse events being consistent with known effects of myeloablative chemotherapy, and with no reports of severe or life-threatening side effects.
The gene therapy led to a robust and sustained increase in fetal hemoglobin levels, accounting for a median of 30.5% of all hemoglobin levels, and being detected in a median of 70.8% of red blood cells. Mean levels of fetal hemoglobin per red blood cell were also uniformly high.
Based on these laboratory findings, “we predict that the patients in this study will have protection from sickling to prevent or significantly ameliorate both acute and chronic complications of sickle cell disease,” the researchers wrote.
Notably, all patients remained free from VOCs, acute chest syndrome, and strokes since the treatment was given. Other SCD complications, such as priapism (prolonged, often painful erection), were also reduced.
BCH-BB694’s use also prevented a need for blood transfusions in two patients who had been receiving them regularly to avoid a stroke. One patient with a rare blood vessel disorder continued to receive predefined blood transfusions due to a potentially higher risk of stroke, but on a less frequent basis than before treatment.
“The initial results of this trial provide validation that BCL11A … can be targeted to lead to successful [fetal hemoglobin] induction in humans,” the researchers wrote.
Additional follow-up data will help determine BCH-BB69’s long-term beneficial effects, they noted.
This type of microRNA-based gene therapy approach “has potential implications for other diseases that could benefit from downregulation of gene expression rather than addition of a gene,” the team wrote.
The study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health.
A separate Phase 1/2 trial with a different approach in targeting the BCL11A gene also recently released promising findings in people with severe SCD. The therapy being investigated here, CTX001, uses the CRISPR-Cas9 gene editing tool to inactivate BCL11A in patient’s blood cell precursors.
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